1. Field of the Invention
The present invention is concerned with pharmaceutical compositions and methods for preventing, inhibiting or reducing inflammation in humans or in domestically useful animals, using muramyl peptides. More specifically, acylmuramyl and acyl desmethylmuramyl dipeptides are particularly useful.
2. Prior Art
Anti-inflammatory activity has been demonstrated for compounds representing a number of structural classes; for example, the corticosteroids, aspirin and related compounds, derivatives of aryl acetic and aryl pyruvic acid and relatives of phenylbutazone. However, no representative of any of these classes is regarded as ideal.
It has recently been found that crude acetylated glycoprotein cell wall fragments from a number of bacteria can be used to reduce inflammation (French Pat. Nos. 2,396,018; 2,396,020, and 2,405,298, and U.S. Pat. No. 4,154,821).
The anti-inflammatory activity of glucosamine in the gastro-intestinal tract has been described in U.S. Pat. No. 4,006,224. Japanese Pat. No. 54/055455 describes the anti-inflammatory and analgesic activity of glucosamine acylated with a 2-(p-isobutylphenyl)propionyl moiety. The zinc salts of acetylated or unacetylated glucosamine which is also the acetal derivative of an alkyl mercaptan are anti-inflammatory, according to Japanese Pat. No. 53/031627. Acetyl glucosamine is useful in treatment of degenerative articular diseases, as disclosed in French Pat. No. 2,016,182.
The invention herein relates to the surprising finding that a class of compounds, muramyl and desmethylmuramyl dipeptides heretofore useful only as adjuvants, possesses anti-inflammatory activity. This result is particularly unexpected because inflammation is a frequent side effect of adjuvant compounds; "adjuvant arthritis", in fact, forms the basis for a secondary screening test for anti-inflammatory agents. (Hirschelmann, et al, Wiss. Martin Luther Univ-Halle-Wittenberg-Math, Naturwiss. Reihe. 27(6) 35-49 (1978)).
The seminal work in this class of compounds, as assayed by their adjuvant activity was the preparation, by Merser et al, of N-acetylmuramyl-L-alanyl-D-isoglutamine. (Biochem. Biophys. Res. Commun. 66:1316, 1975). This compound, also known as MDP, was shown to be the minimal adjuvant structure which could substitute for mycobacteria as Freunds Complete Adjuvant. Ellouz et al, (Biochem. Biophys. Res. Commun. 59:1317, 1974).
Previous patents have described the preparation and use as adjuvants of muramyl and desmethylmuramyl dipeptides which are variations on a general formula: ##STR2## where each of R.sub.1 through R.sub.5 can independently be hydrogen or a variety of acyl, alkyl, aryl, or arylalkyl substituents any of which may be further substituted. Such compounds have been described in the following patents: Belgian Pat. Nos. 834,753; 834,754; 847,103; 849,214; German Pat. Nos. 2,710,455; 2,922,533; 2,747,379; 2,912,865; French Pat. Nos. 2,355,505; 2,358,159 and 2,375,249; European Patent Office Pat. Nos. 4,512 and 2,677; Japanese Pat. Nos. 54/063016; 54/073729 and 55/019236 and U.S. Pat. Nos. 4,082,735 and 4,082,736.